Focal segmental glomerulosclerosis (FSGS) is characterized by the accumulation of fibrotic proteins in glomeruli, initially affecting only some glomeruli (focal) and affecting only a segmental portion of the affected glomeruli. FSGS includes the follow entities: 1) idiopathic FSGS, including a particularly aggressive collapsing variant; 2) HIV-associated FSGS; and 3) hyperfiltration FSGS associated with reduced nephron mass. The most commonly accepted model of pathogenesis proposes that injury to the podocyte (the visceral glomerular epithelial cell) initiates a process that leads to glomerular scarring. This model is supported by recent findings that familial FSGS can be associated with mutations in podocyte-expressed genes WT-1, actinin 4, and podocin. African-Americans are at a three-fold risk of developing idiopathic FSGS, and at an 18-fold increased risk for HIV-associated FSGS, although most patients lack a family history of FSGS. These observations have suggested a genetic basis for increased susceptibility, but the relevant loci have not been identified.[unreadable] [unreadable] We hypothesize that a gene or genes present in people of African descent, predisposes to FSGS following exposure to particular environmental factors such as infection by parvovirus B19, SV40 or HIV-1. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued four groups of African Americans in this study: 1) idiopathic FSGS (n=195); 2) donor controls (n=393); 3) HIV-associated FSGS (n=53); and 4) HIV controls (n=244). We also accrued 131 European Americans with FSGS and 282 normal donor European Americans as a control group. All individuals in the European American study group tested negative or lacked risk factors for HIV-1 infection.[unreadable] [unreadable] We are using a candidate gene approach to identify markers associated with the FSGS phenotype. Mutations in NPHS2 have been associated with nephrotic syndrome, including focal segmental glomerulosclerosis. NPHS2 encodes podocin, a protein expressed exclusively on the glomerular podocyte. Podocin is an integral membrane protein that is located on the foot processes adjacent to the slit diaphragms that are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space. Podocin interacts with other podocyte proteins, including recruiting nephrin to lipid rafts within the plasma membrane and CD2AP.[unreadable] [unreadable] Cases and controls have been genotyped for twelve NPHS2 single nucleotide polymorphisms (SNPs). As FSGS is associated with HIV-1 in African Americans we analysed the HIV- group and the HIV+ group separately and then combined both groups in order to analyze all FSGS cases versus controls. The association between NPHS2 SNP alleles and FSGS was evaluated comparing allele and genotype frequencies between cases and controls. One SNP was associated with FSGS in the HIV+ group (P=0.015) and the case control group (regardless of HIV status) (P=0.008) for the dominant model in African Americans and two other SNPs (P=0.036 were associated with FSGS in European Americans. Haplotype analyses have been performed and in African Americans there is one haplotype that appears to be protective whereas in European Americans a different haplotype appears to increase susceptibility to FSGS. Analyses also revealed a strong association between haplotype and age of FSGS onset.[unreadable] [unreadable] Recently we reported that variants in the Wilms' tumor gene WTI are associated with FSGS in African Americans. The Wilms' tumor gene is important for nephrogenesis and gonadal growth and mutations within the gene cause Denys-Drash and Frasier syndromes, which are characterized by glomeruli scarring. Immediately upstream to the Wilms' tumor gene is the WIT1 that shares a promoter with WT1.